Glucosides and process of making the same



. Patented May 22, 1945 GLUCOSIDES AND rnocass or MAKING THE SAME Karl Miescher, ltiehen, and Jules Heer, Basel- "Switzerland, and Werner Fischer, Summit,

N. .L, assignors to Ciba Pharmaceutical Products Inc., Summit, N. J., a corporation of New Jersey No Drawihg. Original application March 25,

1941, Serial No. 385,196. Divided and this application April 2a, 1943, Serial No. 484,924

.AltClaims. (Cl. 260-210) This invention relates to the manufacture of new sugar derivatives of non-steroids having the effect of steroid hormones by treating such n'onthe presence of a catalyst useful in furthering etheriflcation.

As parent material there may be-used any nonsteroid, having the efiectbf steroid hormones.

which contains at least one reactive hydroxyl group. The following compounds may, be especially named as examples: alkylor alkenyl-polyphenols such as 4:4'-dihydroxy-a:p-diethy1-di phenylethane, 4:4'-azp-tetrahydroxy-azp-diethyldiphenylethane, dianols, hydroxy-compounds of the stilbene series such as 4:4'-dihydroxystilbene, a:a'-dialkyl-, -dialkenyl-, -dialkinyl-,.

-alkylarylor -diaryl-4:4'-dihydroxystilbene such as a:cJ-dimethyl-4:4'-dihydroxystilbene,'

haw-ethyl 4:4'-dihydroxystilbene, u:'-diisopropyl-4 :4f -dihydroxystil-bene, J a:'-diethiny1-4:4'- dihydroxystilbene or a:-diphenyl-4:4"-dihydroxystilbene, further a-mono-alkyb, -a1kenyl-, -alkinylor -aryl-'4:4'-dihydroxystilbenes such as methyl-, ethylethenyl-, ethiny1-, allylor phenyl-4:4'-dihydroxystilbenes. Further also hysteroids with an etherifying sugar derivative in droxy-compounds of the polyphenylethane series which are substituted in aand/or lad-position by alkenyl, alkinyl or alkylidenes, such as for example 3 4- (4' :4'-'-dihydroxy-diphenyl) -2 4-hexadiene, 2:3-(4':4"-dihydroxydiphenyl)-1:3 -butadiene, a a'-diethinyl-4' :4 -dihydroxy-diphenylethane, a:'-dial1yl-2' ;2' '-dihydroxydiphenylethane, a-ethinyl 4' :4" dihydroxy diphenylethane, ethylidene- 4' :4" :4' trihydroxy triphenylethane.

Etherifying sugar derivatives include such.

.- ods in presence of a, catalyst useful in furthering etherification, such as are described for example in Richter-Anschiitz,chemie der. Kohlenstoifverbindungen, vol. 2,- 1st half, page 359 (1935). This text-book describes for example the action of hydrochloric acid on alcoholic sugar solutions, the reaction of alcohois with 1:2-oxides of sugars and the manufacture of phenolglycosides from phenols and sugar acetates by zinc chloride or para-toluene sulfonic acid. But other known catalysts furthering the etheriflcation may also be used, for example silver oxide, silver carbonate, mercury salts such as mercury oxide,

mercury acetate (of. Berichte, vol. 62, page 990/1929) and. mercury succinate, emulsin and the glucosidase of yeast.

The new compounds may contain one or more saccharide residues in the molecule and also hydroxyl groups'which are still free or have been esterifled or etherified. The saccharide residue may also be present in the form of derivatives, for instance in the form of their acylates.

The new compounds are characterised by their better solubility in water and are-useful in thempeutics.

The following examples illustrate the invention:

Example 1 1 1 part by weight or! 4:4'-dihydro'xy-:p-diethylstilbene, 3 parts of penta-acetylglucose and 0.1 part of paratoluenesulfonic acid and 10 parts of benzene are boiled for iivehours. The solution is then taken up in benzene and washed with dilute caustic soda lye and water and then dried over-sodium sulfate. After evaporating the benzene finally in -a vacuum there is obtained the octa-acetyl-bis-glucoside of dihydroxydiethylstilbene in the form of colorless crystals. F. 227-230". It may be recrystallised from methanol or ethanol. o

The acetyi derivative may be saponifled by heating a methanol solution thereof with 1 part of a solution of 1 part of sodium in parts of methanol for a short time. Water-is then added, whereby 4f:4'-bis-(p-glucoside) mp-diethylstilbene is precipitated in the form of a white powder. It may be'recrystallised from butanol and melts with decomposition at about 245. The

saponification may also be effected with other hydrolising agents, for example sodium hydroxide.

In analogous manner there may be obtained.

The said saccharides can equally well be obtamed by way of other etherifying sugar derivatives, such as the corresponding acetohalogen sugars or acetyl sugars even in presence of other catalysts furthering etheriflcation, for instance zinc chloride, silver carbonate, mercury salts such as mercury acetate, mercury oxide and mercury succinate, eniulsin or the gluoosidase of yeast.

or 4 :4'-bis (p-gentiobiosido) -d-gluof polyanols, for instance dianol, alkyl-monoand poly-phenols, such as 4:4-dihydroxy-a:'p-

diethyl diphenylethane, 4:4 -a p-tetrahydroxyo: :fi-diethyl-diphenylethane, hydroxycompounds of the polyphenylethane series which are substituted in-aand/or cU-position by alkenyl, alkinyl or aikylicles, such as for example aZoU-diGthlHYl- 4 :4"-dihydroxy diphenylethane, a-ethenyl-2'- hydroxydiphenyleth'ane, a ethylidene 4:4':4"-

trlhydroxy triphenylethane, may be obtained.

Example 2 I In quite similar manner the sugar derivatives plication Serial No. 257,736. filed February 21, A

v 1939 (now U. S. PatentNo. 2,270,380) I What we claim is: 1. A process for the manufacture of glucosides which comprises reacting a compound of the formula:

E111. c'aH of hydrogen, lower aliphatic acyl and aroyl, with an etherifying monosaccharide derivative selectzoate of the 4:4-dihydroxy-u:fl-diethyl-diphen- 2n ylethane which is sparingly soluble in ether is separated nearly quantitatively. The dibenzoate is suction-filtered and washed with ether. The ether solution is washed first with dilute sulfuric finally with water. After drying it is evaporated and the oily residueis taken up in aqueous methanol. After standing for some time the monobenzoate of the 4:4'-dihydroxy-a:p-diethyl-diphenylethane crystallises, which after recrystallisation from methanol melts at 123-126 C.

5 parts of freshly precipitated and dried silver formula: 1 acid, then with sodium carbonatersclutieaand gs oxide are introduced while stirring into a soluto remove the silver oxide and the silver bromide,

then washed withdilute sulfuric. acid, dilute sodium carbonate solution and water and after drying evaporated in a vacuum. I The monotetraceed from the group consisting of the lower aliphatic acyl and acyloxy-halogen compounds of the monosaccharides and mixed with a catalyst useful in furthering etheriflcation.

2. A process as defined in claim 1, and comprising the further step of treating the resultant product with a hydrolyzing agent.

3. A process for the manufacture of glucosides which comprises reacting a compound of the CIHI wherein R is a member of the group consisting of hydrogen; lower aliphatic acyl and aroyl, with an etherifying glucose derivative selected from 40 which comprises reacting a compound of the tyl-p-glucoside of the 4-hydroxy-4'-benzoxy-:p-

diethyl-diphenylethane after chromatographic purification and recrystallization, melts at 156 C.

1.9 parts of this compound are suspended in 60 parts of methanol and the solution is stirred at room temperature with a solution of 0.3 part of sodium in 30 parts of methanol. After some hours a clear solution is obtained which is ex- 7 actly neutralised with dilute acetic acid and then evaporated to a small volume. By adding water diethyl-diphenylethane, which melts at 203-204 formula:

can Cs I H0 OR- wherein R is a member ofthe group consisting of 6. A process for the manufacture of glucosides,

' which comprises reacting a compound of the l the mono-p-glucoside of the 4:4'-dihydroxy-:p-

Q]. when recrystallised from aqueous methanol, is

o ined.

' The same product can be obtained in analogous propionate of the 4:4' dihydroxy-ezp-diethyldiphenylethane instead of with the monq-benzoate, the corresponding mono-tetracyl-p-glucoside manner by way of the mono-acetate or monoc0 ylethanes being thereby formed as intermediate other monosaccharides, like mannose, arabinose etc. using an etherifying derivative of them and a catalyst usefuli-n furthering etherification. This application is a division of our application Serial No. 385,196, fiied'March 25, 1941,

formula:

can our,

wherein R is-a member of the group consisting of hydrogen, lower aliphatic acyl and aroyl. with wherein R' is a member of the group. consisting of hydrogen, lower aliphatic acyl and aroyl, with pentaacetyl glucose mixed with paratoluenesulfonic acid and then treating the product thus which is itself a continuation in part of our apobtained with sodium ethylate 8. The compounds of the formula: wherein R is a lower aliphatic acylated glucose cm. can radical an R is a lower aliphatic acyl radical. QJ J 11. The compounds of the formula I 01m 0,11. H i m wherein R is a member of the group consisting k A of a tree and a lower aliphatic ac'ylated monosaccha de radi and is member 0 t wherein R is a lower aliphatic acylated glucose v roup consist o hy ro en. lower aliphat radical and R is a lower aroyl radical. acyLlower aroyl, and tree and lower aliphatic 12,- h 1 14 of 4:4'-dihydrolxyacylated monosaccharide radicals. azp-diethyl-diphenylethane, melting at 203- 9. The compounds of the formula: 204 C. 1

0,11. 0,11. 13. The mono-tetracetyl-fl-glucoside of 4:4-

fi $0 dihydroxy-a:p-diethyl-diphenylethane. A ll 14. The mono-tetracetyl-fl-glucoside of 4-hy- H droxy 4'- benzoxy-mp-diethyl diphenylethane, wherein R is a member of the group consisting melting at 156 C.

of a free and a lower aliphatic acylated glucose KARL MIESCHER. radical. j v I JULES HEER.

10; The compounds of the formula: ID i WERNER FISCHER.

I can can 

